Cystic Fibrosis, Exocrine Pancreatic Insufficiency
Conditions
Keywords
CF, Cystic Fibrosis, EPI, Exocrine Pancreatic Insufficiency, Pancreatic, Enzyme, PEP
Brief summary
The primary efficacy objective of this study is to compare the coefficient of fat absorption (CFA) following oral administration of Aptalis Pharma's (formerly Eurand Pharmaceuticals) pancreatic enzyme product (PEP) capsules and placebo in participants with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI).
Detailed description
This is a randomized, double-blind, placebo-controlled, 2-treatment, crossover, multicenter trial in participants with CF and EPI. The study consists of a screening period (1 to 14 days), a washout period (2 days), a dose titration/stabilization period (6 to 9 days), a blinded randomized treatment period (6 to 7 days), an open-label normalization period 1 (5 to 14 days), a blinded crossover treatment period (6 to 7 days), followed by an open-label normalization period 2 (7 days). The order of treatments (placebo followed by EUR-1008 \[APT-1008\] or EUR-1008 \[APT-1008\] followed by placebo) will be determined by randomization at the beginning of randomization treatment period only and will be carried through the crossover treatment period. The starting dose will be 1,000 lipase units per kilogram per meal (lipase units/kg/meal), which will be titrated to control symptoms of EPI, with the total dose not exceeding 10,000 lipase units/kg/day.
Interventions
EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule will be given orally daily in first double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for first double-blind intervention period will be 2 days home treatment and 3 to 5 days hospital treatment.
DRUGPlacebo
Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule will be given orally daily in second double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for second double-blind intervention period will be 2 days home treatment and 3 to 5 days hospital treatment.
Sponsors
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with age greater than or equal to (\>=) 7 years at the time of enrollment * Participants with weight 70 kg or less and be in an adequate nutritional status as indicated by a body mass index (BMI) \>=20 kg/m\^2 for ages 18 and above, or a BMI above the twenty fifth percentile for participants aged 7 to 17 years * Participants with confirmed diagnosis of CF who have 2 clinical features consistent with CF, and have either a genotype with 2 identifiable mutations consistent with CF or a sweat chloride concentration that is more than 60 milliequivalent per liter by quantitative pilocarpine iontophoresis * Participants with confirmed diagnosis of EPI who are currently receiving treatment with a commercially available PEP and have documented with a fecal elastase of \<100 microgram per gram stool (if no documentation was available, a stool sample was taken at Screening for determination of fecal elastase). * Clinically stable participants with no evidence of acute respiratory disease or any other acute condition * Participants who are willing and able to interrupt current CF treatment for CF-related malabsorption along with any medications that may affect gastric motility or stomach power of hydrogen (pH) * Participants 18 years of age and older had to a) understand the requirements of the study, b) provide written informed consent, c) agree to abide by the study restrictions, and d) return for the required assessments * Participants 7 to 17 years of age must have a parent(s) or legal guardian who provides written informed consent, agree to abide by the study restrictions * Females participants of childbearing potential must have a negative serum pregnancy test at screening and must agree to use adequate birth control during the study
Exclusion criteria
* Participants with fibrosing colonopathy, hyperuricemia or hyperuricosuria * Participants who are allergic to pork or other porcine PEPs * Participants with forced expiratory volume (FEV1) \<30 percent of predicted FEV1 at screening * Participants with any acute systemic administration of an antibiotic for any reason in the previous 4 weeks; however, a low stable dose of an antibiotic or chronic treatment with an inhalatory antibiotic is allowed * Participants with hepatic insufficiency as defined by history or presence of ascites or serum albumin level of \< 3.0 milligram/deciliter, or a coagulopathy with an international normalized ratio that is greater than 1.7 * Participants who have used an acute dose of any steroid in the previous 2 weeks; however, low chronic doses of a steroid is allowed * Participants with history of or current diagnosis of distal ileal obstruction syndrome (DIOS) as evidenced or suggested by constipation, abdominal pain, anorexia, early satiety, recurrent vomiting, and palpable fecal mass on physical examination (the absence of DIOS will be confirmed by an X-ray of the abdomen taken at screening) * Participants with any solid organ transplant or surgery affecting the bowel. Participants with a history of appendectomy and inguinal (non-incarcerated) hernioplasty or meconium ileus without the need for bowel resection could be enrolled. Gastrointestinal-tube-fed patients, in absence of dumping syndrome, were also eligible * Participants with history of or current screening evaluation of hyperglycemia as defined by an 8-hour fasting blood glucose (FBG) of \>126 mg/dL, or of CF-related diabetes as determined according to the Cystic Fibrosis Foundation (CFF) Consensus Conference of January 1999 (Section IX Part II), that is: a) FBG \>126 mg/dL (7.0 millimoles per liter \[mmol/L\]) on two or more occasions b)FBG \>126 mg/dL (7.0 mmol/L) plus casual (without regard to time of day or last meal consumed) glucose level \>200 mg/dL (11.1 mmol/L) c)Casual (previously called random) glucose levels \>200 mg/dL (11.1 mmol/L) on two or more occasions with symptoms * Participants using an enzyme preparation in excess of 10,000-lipase units/kg/day * Participants using an immunosuppressive drug * Participants who are expecting an inability to tolerate the washout period and/or the placebo treatment * Participants participating in an investigational study of a drug, biologic, or device not currently approved for marketing, within 30 days of screening visit * Female participants who are pregnant or breastfeeding, or unwilling to use effective birth control during study * Participants with any condition that would, in the investigator's opinion, limit the participant's ability to complete the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Coefficient of Fat Absorption (CFA%) | Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods | Percent CFA was calculated as (\[fat intake - fat excretion\]/fat intake)multiplied by 100, determined in the stools collected during the 72-hour hospitalization period. Mean percent CFA was calculated for Day 3 to Day 6 during hospital treatment in first and second double-blind (DB) intervention periods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Coefficient of Nitrogen Absorption (CNA%) | Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods | Percent CNA was calculated as (\[nitrogen intake-nitrogen excretion\]/nitrogen intake)\*100, determined in the stools collected during the 72-hour hospitalization period. Nitrogen intake was calculated as protein intake/6.2. Nitrogen excretion was measured as total fecal nitrogen. Mean percent CNA was calculated for Day 3 to Day 6 during hospital treatment in first and second double-blind intervention periods. |
| Lipid Levels | End of treatment (Day 6 during first and second double-blind intervention periods) | Lipid levels were reported for total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) from fasted blood and urine samples. Mean lipid levels for Day 6 during first and second double-blind intervention periods were calculated. |
| Vitamin A Levels | End of treatment (Day 6 during first and second double-blind intervention periods) | Mean Vitamin A levels for Day 6 during first and second double-blind intervention periods were calculated. |
| Vitamin E Levels | End of treatment (Day 6 during first and second double-blind intervention periods) | Mean Vitamin E levels for Day 6 during first and second double-blind intervention periods were calculated. |
| Percentage of Stool Categorized as Per Consistency | Day 3 up to Day 6 during first and second double-blind intervention periods | Stool consistency was categorized as hard, formed/normal, soft, watery, or overt diarrhea. Percentage of stools of a specific consistency for each participant at first and second double-blind intervention periods was calculated. Mean percentage of stool consistency during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. |
| Mean Number of Abdominal Symptoms | Day 3 up to Day 6 during first and second double-blind intervention periods | Abdominal symptoms included abdominal pain, flatulence and bloating. Symptoms were classified by severity as mild (no impairment of daily activities), moderate (slight impairment of daily activities), or severe (unable to perform daily activities). Mean number of symptom of specific severity per day for each participant was calculated. Mean number of symptoms per day was calculated for Day 3 to Day 6 in first and second double-blind intervention periods for total participants. |
| Mean Daily Number of Stools | Day 3 up to Day 6 during first and second double-blind intervention periods | Mean daily number of stools of each participant was calculated from frequency of stools by the participant per day. Mean daily number of stools during the collection period (Day 3 to Day 6 in first and second double-blind intervention periods) for total participants was summarized. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Visible Oil or Grease in Stool | Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods | Mean percentage of stools with visible oil or grease during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. Percentage was calculated as the number of stools with visible oil or grease divided by the total number of stool per day. |
| Percentage of Stools With Blood | Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods | Mean percentage of stools with blood during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. Percentage was calculated as the number of stools with blood divided by the total number of stool per day. |
Countries
United States
Participant flow
Pre-assignment details
Out of 34 participants who were enrolled and treated during open-label dose titration and stabilization period, 1 participant withdrew from the study before randomization to first double-blind intervention period.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes participants who received EUR-1008 (APT-1008) in open-label dose titration and stabilization phase; and EUR-1008 (APT-1008) first and placebo first after randomization to study treatment. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Dose Normalization Period 1 | Withdrawal by Subject | 0 | 0 | 1 |
| Second Double-blind Intervention Period | Protocol Violation | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 14.9 years STANDARD_DEVIATION 4.75 |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 34 | 16 / 32 |
| serious Total, serious adverse events | 2 / 34 | 0 / 32 |
Outcome results
Primary
Percent Coefficient of Fat Absorption (CFA%)
Percent CFA was calculated as (\[fat intake - fat excretion\]/fat intake)multiplied by 100, determined in the stools collected during the 72-hour hospitalization period. Mean percent CFA was calculated for Day 3 to Day 6 during hospital treatment in first and second double-blind (DB) intervention periods.
Time frame: Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods
Population: Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period. Here N (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) | Percent Coefficient of Fat Absorption (CFA%) | 88.28 percent CFA | Standard Error 2.599 |
| Placebo | Percent Coefficient of Fat Absorption (CFA%) | 62.76 percent CFA | Standard Error 2.639 |
Comparison: P-Value was calculated using analysis of variance (ANOVA) model which included main effects for treatment and sequence and participant nested in sequence as a random effect.p-value: <0.00195% CI: [-31.73, -19.32]ANOVA
Secondary
Lipid Levels
Lipid levels were reported for total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) from fasted blood and urine samples. Mean lipid levels for Day 6 during first and second double-blind intervention periods were calculated.
Time frame: End of treatment (Day 6 during first and second double-blind intervention periods)
Population: Safety population included all participants who received at least 1 dose of study treatment. Here N (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and n signifies participants who were evaluable at specific time point in each treatment arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EUR-1008 (APT-1008) | Lipid Levels | HDL-C: End of Treatment (n=33, 30) | 45.5 milligram/deciliter (mg/dL) | Standard Deviation 10.85 |
| EUR-1008 (APT-1008) | Lipid Levels | TC: End of Treatment (n=33, 30) | 128.8 milligram/deciliter (mg/dL) | Standard Deviation 28.98 |
| Placebo | Lipid Levels | HDL-C: End of Treatment (n=33, 30) | 37.2 milligram/deciliter (mg/dL) | Standard Deviation 9.23 |
| Placebo | Lipid Levels | TC: End of Treatment (n=33, 30) | 109.1 milligram/deciliter (mg/dL) | Standard Deviation 29.76 |
Secondary
Mean Daily Number of Stools
Mean daily number of stools of each participant was calculated from frequency of stools by the participant per day. Mean daily number of stools during the collection period (Day 3 to Day 6 in first and second double-blind intervention periods) for total participants was summarized.
Time frame: Day 3 up to Day 6 during first and second double-blind intervention periods
Population: Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) | Mean Daily Number of Stools | 1.76 stools per day | Standard Deviation 0.898 |
| Placebo | Mean Daily Number of Stools | 2.66 stools per day | Standard Deviation 1.418 |
Secondary
Mean Number of Abdominal Symptoms
Abdominal symptoms included abdominal pain, flatulence and bloating. Symptoms were classified by severity as mild (no impairment of daily activities), moderate (slight impairment of daily activities), or severe (unable to perform daily activities). Mean number of symptom of specific severity per day for each participant was calculated. Mean number of symptoms per day was calculated for Day 3 to Day 6 in first and second double-blind intervention periods for total participants.
Time frame: Day 3 up to Day 6 during first and second double-blind intervention periods
Population: Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Bloating: Moderate | 0.05 symptoms per day | Standard Deviation 0.191 |
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Flatulence: Severe | 0.00 symptoms per day | Standard Deviation 0 |
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Flatulence: Mild | 0.40 symptoms per day | Standard Deviation 0.688 |
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Pain: Mild | 0.16 symptoms per day | Standard Deviation 0.433 |
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Bloating: Severe | 0.00 symptoms per day | Standard Deviation 0 |
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Pain: Moderate | 0.08 symptoms per day | Standard Deviation 0.379 |
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Flatulence: Moderate | 0.08 symptoms per day | Standard Deviation 0.275 |
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Pain: Severe | 0.00 symptoms per day | Standard Deviation 0.022 |
| EUR-1008 (APT-1008) | Mean Number of Abdominal Symptoms | Bloating: Mild | 0.10 symptoms per day | Standard Deviation 0.3 |
| Placebo | Mean Number of Abdominal Symptoms | Pain: Severe | 0.09 symptoms per day | Standard Deviation 0.228 |
| Placebo | Mean Number of Abdominal Symptoms | Bloating: Mild | 0.31 symptoms per day | Standard Deviation 0.718 |
| Placebo | Mean Number of Abdominal Symptoms | Bloating: Moderate | 0.10 symptoms per day | Standard Deviation 0.329 |
| Placebo | Mean Number of Abdominal Symptoms | Bloating: Severe | 0.09 symptoms per day | Standard Deviation 0.495 |
| Placebo | Mean Number of Abdominal Symptoms | Flatulence: Mild | 0.70 symptoms per day | Standard Deviation 1.134 |
| Placebo | Mean Number of Abdominal Symptoms | Flatulence: Moderate | 0.41 symptoms per day | Standard Deviation 1.16 |
| Placebo | Mean Number of Abdominal Symptoms | Flatulence: Severe | 0.18 symptoms per day | Standard Deviation 0.719 |
| Placebo | Mean Number of Abdominal Symptoms | Pain: Mild | 0.62 symptoms per day | Standard Deviation 0.901 |
| Placebo | Mean Number of Abdominal Symptoms | Pain: Moderate | 0.32 symptoms per day | Standard Deviation 0.754 |
Secondary
Percentage of Stool Categorized as Per Consistency
Stool consistency was categorized as hard, formed/normal, soft, watery, or overt diarrhea. Percentage of stools of a specific consistency for each participant at first and second double-blind intervention periods was calculated. Mean percentage of stool consistency during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized.
Time frame: Day 3 up to Day 6 during first and second double-blind intervention periods
Population: Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EUR-1008 (APT-1008) | Percentage of Stool Categorized as Per Consistency | Formed/Normal | 53.86 percentage of stools | Standard Deviation 37.253 |
| EUR-1008 (APT-1008) | Percentage of Stool Categorized as Per Consistency | Watery | 0.36 percentage of stools | Standard Deviation 1.421 |
| EUR-1008 (APT-1008) | Percentage of Stool Categorized as Per Consistency | Soft | 29.24 percentage of stools | Standard Deviation 34.096 |
| EUR-1008 (APT-1008) | Percentage of Stool Categorized as Per Consistency | Overt diarrhea | 0.00 percentage of stools | Standard Deviation 0 |
| EUR-1008 (APT-1008) | Percentage of Stool Categorized as Per Consistency | Hard | 16.54 percentage of stools | Standard Deviation 29.637 |
| Placebo | Percentage of Stool Categorized as Per Consistency | Overt diarrhea | 0.82 percentage of stools | Standard Deviation 3.67 |
| Placebo | Percentage of Stool Categorized as Per Consistency | Hard | 6.24 percentage of stools | Standard Deviation 18.845 |
| Placebo | Percentage of Stool Categorized as Per Consistency | Formed/Normal | 33.25 percentage of stools | Standard Deviation 34.414 |
| Placebo | Percentage of Stool Categorized as Per Consistency | Soft | 57.11 percentage of stools | Standard Deviation 36.105 |
| Placebo | Percentage of Stool Categorized as Per Consistency | Watery | 2.59 percentage of stools | Standard Deviation 4.836 |
Secondary
Percent Coefficient of Nitrogen Absorption (CNA%)
Percent CNA was calculated as (\[nitrogen intake-nitrogen excretion\]/nitrogen intake)\*100, determined in the stools collected during the 72-hour hospitalization period. Nitrogen intake was calculated as protein intake/6.2. Nitrogen excretion was measured as total fecal nitrogen. Mean percent CNA was calculated for Day 3 to Day 6 during hospital treatment in first and second double-blind intervention periods.
Time frame: Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods
Population: Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period. Here N (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) | Percent Coefficient of Nitrogen Absorption (CNA%) | 87.17 percent CNA | Standard Error 2.179 |
| Placebo | Percent Coefficient of Nitrogen Absorption (CNA%) | 65.67 percent CNA | Standard Error 2.213 |
Comparison: P-Value was calculated using analysis of variance (ANOVA)model which included main effects for treatment and sequence and participant nested in sequence as a random effect.p-value: <0.00195% CI: [-26.85, -16.14]ANOVA
Secondary
Vitamin A Levels
Mean Vitamin A levels for Day 6 during first and second double-blind intervention periods were calculated.
Time frame: End of treatment (Day 6 during first and second double-blind intervention periods)
Population: Safety population included all participants who received at least 1 dose of study treatment. Here N (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) | Vitamin A Levels | 422.3 microgram per liter (mcg/L) | Standard Deviation 111.67 |
| Placebo | Vitamin A Levels | 363.2 microgram per liter (mcg/L) | Standard Deviation 100.33 |
Secondary
Vitamin E Levels
Mean Vitamin E levels for Day 6 during first and second double-blind intervention periods were calculated.
Time frame: End of treatment (Day 6 during first and second double-blind intervention periods)
Population: Safety population included all participants who received at least 1 dose of study treatment. Here N (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) | Vitamin E Levels | 8.25 mg/L | Standard Deviation 3.115 |
| Placebo | Vitamin E Levels | 6.69 mg/L | Standard Deviation 2.648 |
Other Pre-specified
Percentage of Stools With Blood
Mean percentage of stools with blood during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. Percentage was calculated as the number of stools with blood divided by the total number of stool per day.
Time frame: Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods
Population: Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) | Percentage of Stools With Blood | 0.17 percentage of stools with blood per day | Standard Deviation 0.174 |
| Placebo | Percentage of Stools With Blood | 1.13 percentage of stools with blood per day | Standard Deviation 4.647 |
Other Pre-specified
Percentage of Visible Oil or Grease in Stool
Mean percentage of stools with visible oil or grease during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. Percentage was calculated as the number of stools with visible oil or grease divided by the total number of stool per day.
Time frame: Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods
Population: Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) | Percentage of Visible Oil or Grease in Stool | 6.78 percentage of visible oil or grease/day | Standard Deviation 17.354 |
| Placebo | Percentage of Visible Oil or Grease in Stool | 27.97 percentage of visible oil or grease/day | Standard Deviation 33.571 |